Four-dimensional computed tomography is useful for detection of apical sparing of cardiac amyloidosis.

A 73-year-old male was admitted because of recurrent syncope. He was diagnosed with transient bradycardia caused by a 2:1 atrioventricular block, and he underwent cardiac computed tomography (CT) using 320 detector-row CT to screen for coronary artery disease. Significant coronary artery stenosis was not detected, but diffuse late iodinate enhancement was found on the epi-myocardium and endo-myocardium of the interventricular septum, and endo-myocardium of the anterior and lateral left ventricular (LV) myocardium (LVM) on CT. The ejection fraction and global longitudinal strain (LS) of LVM were 53.97% and - 9.87% on CT. Apical sparing was present, meaning the LS of LV apical segments were preserved compared with basal segments on CT. Pathological findings of LVM demonstrated loss of myocardial cells and extra-cellular amyloid deposition on the direct fast scarlet staining. He was finally diagnosed with transthyretin amyloidosis.

Keratin 6A is expressed at the invasive front and enhances the progression of colorectal cancer.

Keratins are intermediate filament proteins in epithelial cells, and they are important for cytoskeletal organization. Keratin 6A (KRT6A), classified as a type II keratin, is normally expressed in stratified squamous epithelium and squamous cell carcinomas. Little is known about the expression and role of KRT6A in adenocarcinomas. We investigated the clinicopathological and molecular biological significance of KRT6A in colorectal adenocarcinoma. Immunostaining of our institution's colorectal adenocarcinoma cases demonstrated that KRT6A showed significantly stronger expression at the invasive front than the tumor center (p < 0.0001). The high-KRT6A-expression cases (n = 47) tended to have a high budding grade associated with significantly worse prognoses. A multivariate analysis revealed that the KRT6A expression status was an independent prognostic factor for overall survival (p = 0.0004), disease-specific survival (p = 0.0097) and progression-free survival (p = 0.0033). The correlation between KRT6A and patient prognoses was also validated in an external cohort from a published dataset. To determine the function of KRT6A in vitro, KRT6A was over-expressed in three colon cancer cell lines, DLD-1, SW620, and HCT 116. KRT6A overexpression increased migration and invasion in DLD-1, but did not in SW620 and HCT116. In three-dimensional sphere-forming culture, KRT6A expression enhanced the irregular protrusion around the spheroid in DLD-1. Our findings in the present study indicated that KRT6A expression is a valuable prognostic marker of colorectal cancer and KRT6A may be involved the molecular mechanism in the progression of invasive areas of colorectal cancer.

ECM1 and KRT6A are involved in tumor progression and chemoresistance in the effect of dexamethasone on pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) has a very poor prognosis. Neoadjuvant chemotherapy is an effective PDAC treatment option, but chemotherapy causes unfavorable side effects. Glucocorticoids (e.g., dexamethasone [DEX]) are administered to reduce side effects of chemotherapy for solid tumors, including pancreatic cancer. Glucocorticoids have both beneficial and detrimental effects, however. We investigated the functional changes and gene-expression profile alterations induced by DEX in PDAC cells. PDAC cells were treated with DEX, and the cell proliferation, migration, invasion, and chemosensitivity to gemcitabine (GEM) were evaluated. The results demonstrated decreased cell proliferative capacity, increased cell migration and invasion, and decreased sensitivity to GEM. A comprehensive genetic analysis revealed marked increases in ECM1 and KRT6A in DEX-treated PDAC cells. We evaluated the effects of ECM1 and KRT6A expression by using PDAC cells transfected with those genes. Neither ECM1 nor KRT6A changed the cells' proliferation, but each enhanced cell migration and invasion. ECM1 decreased sensitivity to GEM. We also assessed the clinicopathological significance of the expressions of ECM1 and KRT6A in 130 cases of PDAC. An immunohistochemical analysis showed that KRT6A expression dominated the poorly differentiated areas. High expressions of these two proteins in PDAC were associated with a poorer prognosis. Our results thus demonstrated that DEX treatment changed PDAC cells' functions, resulting in decreased cell proliferation, increased cell migration and invasion, and decreased sensitivity to GEM. The molecular mechanisms of these changes involve ECM1 and KRT6A, whose expressions are induced by DEX.

Utility of prophylactic clipping after colorectal cold snare polypectomy in patients on oral antithrombotic agents.

BACKGROUND AND AIMS: There is no consensus on the effectiveness of prophylactic clipping after colonic cold snare polypectomy (CSP). This study aimed to evaluate the utility of prophylactic clipping in preventing delayed bleeding (DB) after colorectal CSP in patients on antithrombotic agents. METHODS: We retrospectively recruited consecutive patients on antithrombotic agents who underwent colorectal CSP in Chiba University Hospital. The DB rate was compared between patients with and without prophylactic clipping. RESULTS: The study included 133 patients (422 polyps) requiring prophylactic clipping and 85 patients (282 polyps) not requiring prophylactic clipping. There were no significant differences in DB and hematochezia rates between the groups. By weighted logistic regression analysis, the odds ratio of hematochezia was 0.557 (95% confidence interval, 0.225-1.378; P = .205) in patients without clipping compared to those with clipping. CONCLUSIONS: Prophylactic clipping may not be necessary to prevent DB after colorectal CSP in patients on antithrombotic agents.

Imprint Cytology of Tall Cell Carcinoma with Reversed Polarity of the Breast: A Case Report.

INTRODUCTION: Tall cell carcinoma with reversed polarity (TCCRP) is a rare histologic subtype of breast cancer that was newly categorized in 2020. TCCRP is a relatively novel tumor, and there are no detailed reports about its cellular morphology. We were able to obtain imprint cytological specimens from fresh TCCRP tissue, and we provide our detailed observations. CASE PRESENTATION: The patient was a 73-year-old Japanese female with a 15-mm mass in her right breast. After invasive breast carcinoma was diagnosed based on a core needle biopsy, a lumpectomy was performed. The pathological examination revealed TCCRP, and Sanger sequencing detected IDH2 p.R172M hotspot mutation, which is characteristic of TCCRP. Soon after the surgery, the lumpectomy specimen was sliced before fixation for use in a clinical trial, and imprint cytological materials were obtained from the tumor's cut surface. Cytologically, the tumor showed papillary-like cell clusters and isolated cells with moderate cellularity. Neoplastic cell aggregates and clusters with thick vascular cores as the axis or with delicate fibrovascular stroma were observed. Most of the neoplastic cells were cuboidal-to-columnar in shape, with mildly to moderately irregularly shaped blunt nuclei. Some intranuclear cytoplasmic inclusions and nuclear grooves were present, resembling the nuclear findings of papillary thyroid carcinoma. The most characteristic finding was the columnar cell clusters with apically located nuclei, giving the impression of reversed polarity. CONCLUSION: We described cytological findings in TCCRP, a newly classified rare mammary tumor. Most of the characteristic histologic findings were also observed in imprint cytological specimens. Further studies on practical specimens such as fine-needle aspiration are needed for clinical application.

Challenges in the diagnosis of the enigmatic primary adrenal leiomyosarcoma: two case reports and review of the literature.

BACKGROUND: Primary adrenal leiomyosarcoma is a rare and aggressive mesenchymal tumor derived from the smooth muscle wall of a central adrenal vein or its tributaries; therefore, tumors tend to invade the inferior vena cava and cause thrombosis. The great majority of tumors grow rapidly, which makes the disease difficult to diagnose in its early clinical stages and needs differentiation from adrenocortical carcinomas for the selection of chemotherapy including mitotane which causes adrenal insufficiency. CASE PRESENTATION: We presented two patients with adrenal leiomyosarcoma who were referred to our hospital with abdominal pain and harboring large adrenal tumors and inferior vena cava thrombosis. The endocrine findings, including serum catecholamine levels, were unremarkable. These two patients were considered clinically inoperable, and CT-guided core needle biopsy was performed to obtain the definitive histopathological diagnosis and determine the modes of therapy. The masses were subsequently diagnosed as primary adrenal leiomyosarcoma based on the histological features and positive immunoreactivity for SMA (smooth muscle actin), desmin, and vimentin. CONCLUSIONS: Adrenal leiomyosarcoma derived from the smooth muscle wall of a central adrenal vein or its tributaries is rare but should be considered a differential diagnosis in the case of nonfunctioning adrenal tumors extending directly to the inferior vena cava. CT-guided biopsy is considered useful for histopathological diagnosis and clinical management of patients with inoperable advanced adrenal tumors without any hormone excess.

A case of ipsilateral three simultaneous renal cell carcinomas with different histologic types.

Introduction: Few reports have presented sporadic multifocal renal cell carcinomas of different histologic types occurring simultaneously in a single kidney. Here, we present a case of three ipsilateral renal cell carcinomas with three histologic types. Case presentation: A 44-year-old man with end-stage renal disease due to nephrosclerosis was referred to our hospital for an incidental renal tumor. Following the introduction of hemodialysis, enhanced computed tomography revealed a renal tumor suggestive of clear-cell renal cell carcinoma with a cystic component. With a preoperative diagnosis of one renal tumor, he underwent laparoscopic radical nephrectomy. However, pathological examination revealed three renal cell carcinomas with three histological diagnoses: clear-cell, papillary, and clear-cell papillary renal cell carcinomas. Conclusion: Preoperative imaging may not detect all synchronous ipsilateral multifocal renal cell carcinomas. Patients with severe renal function impairment may have synchronous multifocal renal cell carcinomas.

A case of bladder cancer after bilateral lung transplantation following bone marrow transplantation.

Introduction: The incidence of bladder cancer following transplantation is high; however, no previous studies have reported the development of bladder cancer following bone marrow and bilateral lung transplantations. Case presentation: A 42-year-old man who was followed for bilateral lung transplantation due to chronic graft-versus-host disease following bone marrow transplantation complained of gross hematuria. Transurethral resection of the bladder tumor was performed for cT1N0M0 bladder cancer. On the following night, he experienced severe respiratory failure and was intubated. He was discharged on postoperative day 32 with the introduction of home oxygen therapy. The pathological diagnosis was invasive urothelial carcinoma, high-grade, pT1, with urothelial carcinoma in situ. Further treatment could not be performed because of his poor performance status and immunosuppressive state. Conclusion: Vigorous screening for bladder cancer coexisting with other malignancies should be performed for transplant recipients for the early diagnosis and prompt treatment of a relatively aggressive bladder cancer.

Frequency of infiltrating regulatory T-cells in the portal tract of biliary atresia.

PURPOSE: Immunological abnormalities have been hypothesized as a pathogenesis of biliary atresia (BA). We previously investigated the frequency and function of circulating regulatory T-cells (Tregs) and reported no differences compared to controls. However, the local Treg profile remains uncertain. We aimed to investigate the frequency of Tregs in BA liver tissues. METHODS: The number of lymphocytes, CD4+ cells, and CD4+FOXP3+ Tregs infiltrating the portal tract and the percentage of Tregs among CD4+ cells of BA and control patients were visually counted. The correlation between these data and clinical indicators was also examined. RESULTS: The number of lymphocytes, CD4+ cells, and CD4+FOXP3+ Tregs was higher in the BA group. However, the percentage of Tregs among CD4+ cells was similar in both groups. Each parameter was correlated with serum γ-GTP, but there was no clear association with liver fibrosis, jaundice clearance, and native liver survival. CONCLUSION: The number of Tregs infiltrating the portal tract was higher in BA patients. However, the infiltration of lymphocytes was also generally increased. Tregs appear to be unsuccessful in suppressing progressive inflammation in BA patients, despite recruitment to local sites. Investigation of Treg function in the local environment is warranted.

Outcomes for Underwater Endoscopic Mucosal Resection and Endoscopic Submucosal Dissection of 21-30-mm Colorectal Polyps: A Feasible Study.

BACKGROUND AND AIMS: This randomized controlled trial (RCT) was designed to evaluate the short-term outcomes of underwater endoscopic mucosal resection (UEMR) and endoscopic submucosal dissection (ESD) of 21-30 mm colonic polyps. METHOD: We conducted a single-center RCT. Patients diagnosed with suspected colorectal intramucosal carcinoma (21-30 mm and adaptable for both UEMR and ESD) were randomly assigned to the UEMR and ESD groups at a 1:1 ratio. The primary endpoint was the R0 resection rate. We independently performed one-sample tests against the set threshold for each treatment. The significance level was set at p = 0.224. RESULT: Eleven polyps each in the UEMR and ESD groups, respectively, were analyzed. The R0 resection rate (%) was 36 (95% confidence interval 11-69) and 100 (72-100) for UEMR and ESD, respectively, with a significant difference between the two groups (p = 0.002). The p-value against the set threshold for UEMR was 0.743, whereas that for ESD was < 0.001 (one-sample binomial test). The en bloc resection rates (%) were 82 (48-97) and 100 (72-100) for UEMR and ESD, respectively; however, no significant difference was observed (p = 0.167). The mean treatment time (min) was significantly shorter in the UEMR group (8 ± 6) than in the ESD group (48 ± 29) (p = 0.001). CONCLUSION: ESD could achieve a high R0 resection rate, while the en bloc resection rate was comparable between the two treatment techniques with less burden on patients undergoing UEMR for 21-30-mm colorectal polyps. CLINICAL TRIAL REGISTRATION: The study was registered at the Japan Registry of Clinical Trial as jRCT1030210015 and jRCT1030210177.

T1a Renal Cell Carcinoma With Metastasis: Japanese Society of Renal Cancer Retrospective Multi-institute Results.

BACKGROUND/AIM: Small renal cell carcinomas (sRCC) have drastically increased in recent years. Considering that sRCC have heterogeneous biology, it would be clinically relevant if specific clinical or pathological parameters could predict sRCC metastasis. In the present study, we aimed to assess the clinicopathological factors of pathologic T1a RCC (pT1a RCC) with or without metastasis to explore factors predicting metastasis. PATIENTS AND METHODS: The present study included 198 patients with pT1a RCC who underwent radical or partial nephrectomy at fifteen institutions belonging to the Japanese Society of Renal Cancer, between1985 and 2017. Clinicopathological parameters, including age, sex, tumour size, tumour side, histological subtype, histological nuclear grade, lymphovascular invasion, and histological growth patterns, were analysed. RESULTS: Fuhrman grade 3 or 4 tumours and infiltrative tumour growth patterns were significantly higher in patients with metastasis than in those without. The most common site of synchronous metastasis was the bone in patients with pT1a RCC (65.4%), whereas for patients with post-surgery metachronous metastasis (46.2%), it was the lungs. CONCLUSION: Histological growth pattern and nuclear grade are vital for predicting metastasis in pT1a RCC, suggesting careful long-term follow-up for such patients.

Switching mechanism from AR to EGFR signaling via 3-O-sulfated heparan sulfate in castration-resistant prostate cancer.

Androgen deprivation therapy is given to suppress prostate cancer growth; however, some cells continue to grow hormone-independently as castration-resistant prostate cancer (CRPC). Sulfated glycosaminoglycans promote ligand binding to receptors as co-receptors, but their role in CRPC remains unknown. Using the human prostate cancer cell line C4-2, which can proliferate in hormone-dependent and hormone-independent conditions, we found that epidermal growth factor (EGF)-activated EGFR-ERK1/2 signaling via 3-O-sulfated heparan sulfate (HS) produced by HS 3-O-sulfotransferase 1 (HS3ST1) is activated in C4-2 cells under hormone depletion. Knockdown of HS3ST1 in C4-2 cells suppressed hormone-independent growth, and inhibited both EGF binding to the cell surface and activation of EGFR-ERK1/2 signaling. Gefitinib, an EGFR inhibitor, significantly suppressed C4-2 cell proliferation and growth of a xenografted C4-2 tumor in castrated mouse. Collectively, our study has revealed a mechanism by which cancer cells switch to hormone-independent growth and identified the key regulator as 3-O-sulfated HS.

Epithelialization of Free Flap Vascular Pedicles through the Nasal Cavity after Long-term Follow-up: A Case Report.

A 59-year-old man with right maxillary cancer presented with a right buccal fistula and an ectropion of the lower eyelid after multidisciplinary treatment. With no suitable vessels in the right face or neck for anastomosis, we planned reconstruction with a free thinned deep inferior epigastric artery perforator flap using the contralateral left facial artery and vein as the recipient. To simulate the length of the vascular pedicle, we used our original software and determined to use the route passing through the nasal cavity. The vascular pedicle was passed through a tunnel from the medial wall of the right maxillary sinus, through the nasal septum and the medial-frontal wall of the left maxillary sinus, to the left facial artery and vein. The flap survived completely, and facial deformity was corrected. At 1 year postoperatively, there had been concerns about the fragility of the vascular pedicle in the nasal cavity and the possibility of easy bleeding. Endoscopic examination revealed that the vascular pedicle in the nasal cavity was covered by fibrous tissue and multirow lineage epithelium, and an excisional biopsy indicated a low possibility of hemorrhage. Cutting off the vascular pedicle to prevent bleeding may not be necessary because the vascular pedicle through the nasal cavity becomes fibrotic and epithelialized in the surrounding area in the long term.

Tumor localization by Prostate Imaging and Reporting and Data System (PI-RADS) version 2.1 predicts prognosis of prostate cancer after radical prostatectomy.

An improved reading agreement rate has been reported in version 2.1 (v2.1) of the Prostate Imaging and Reporting and Data System (PI-RADS) compared with earlier versions. To determine the predictive efficacy of bi-parametric MRI (bp-MRI) for biochemical recurrence (BCR), our study assessed PI-RADS v2.1 score and tumor location in Japanese prostate cancer patients who underwent radical prostatectomy. Retrospective analysis was performed on the clinical data of 299 patients who underwent radical prostatectomy at Chiba University Hospital between 2006 and 2018. The median prostate-specific antigen (PSA) level before surgery was 7.6 ng/mL. Preoperative PI-RADS v2.1 categories were 1-2, 3, 4, and 5 in 35, 56, 138, and 70 patients, respectively. Tumor location on preoperative MRI was 107 in the transition zone (TZ) and 192 in the peripheral zone (PZ). BCR-free survival was significantly shorter in the PZ group (p = 0.001). In the total prostatectomy specimens, preoperative PI-RADS category 5, radiological tumor location, pathological seminal vesicle invasion, and Grade Group ≥ 3 were independent prognostic factors of BCR. These four risk factors have significant potential to stratify patients and predict prognosis. Radiological tumor location and PI-RADS v2.1 category using bp-MRI may enable prediction of BCR following radical prostatectomy.

Simultaneous development of generalized pustular psoriasis and pemphigoid with multiple autoantibodies in a complete responder of pembrolizumab for lung cancer.

Patients with psoriasis vulgaris have a higher incidence of pemphigoid than the general population. However, there are only a few concise reports on the coexistence of generalized pustular psoriasis (GPP) and pemphigoid. The authors describe a rare case of the simultaneous development of GPP and pemphigoid with multiple autoantibodies (i.e., BP180-C-terminal, 200-kDa protein, and laminin 332 proteins) in a complete responder of immune checkpoint inhibitor (ICI) treatment for lung cancer. Anti-interleukin 17 inhibitors for the GPP and oral corticosteroids at 10 mg/day for the pemphigoid effectively achieved remission in both diseases. It may not be uncommon to detect multiple autoantibodies in patients with pemphigoid; however, the detection of autoantibodies to more than three antigens in a single patient is relatively rare. In the current patient, the severe inflammation of GPP might have generated multiple autoantibodies. In addition, although pembrolizumab achieved a complete response and was discontinued 9 months before the onset of GPP and pemphigoid, the ICI might have affected the development of the two diseases. This case report adds useful information to the limited knowledge regarding the coexistence of GPP and pemphigoid, and aids in a better understanding of the pathological mechanisms and treatment options for such patients. Furthermore, the possibility that more patients may develop multiple autoimmune and autoinflammatory diseases in the era of ICIs should be recognized.

Clinical utility of artificial intelligence assistance in histopathologic review of lymph node metastasis for gastric adenocarcinoma.

BACKGROUND: Advances in whole-slide image capture and computer image analyses using deep learning technologies have enabled the development of computer-assisted diagnostics in pathology. Herein, we built a deep learning algorithm to detect lymph node (LN) metastasis on whole-slide images of LNs retrieved from patients with gastric adenocarcinoma and evaluated its performance in clinical settings. METHODS: We randomly selected 18 patients with gastric adenocarcinoma who underwent surgery with curative intent and were positive for LN metastasis at Chiba University Hospital. A ResNet-152-based assistance system was established to detect LN metastases and to outline regions that are highly probable for metastasis in LN images. Reference standards comprising 70 LN images from two different institutions were reviewed by six pathologists with or without algorithm assistance, and their diagnostic performances were compared between the two settings. RESULTS: No statistically significant differences were observed between these two settings regarding sensitivity, review time, or confidence levels in classifying macrometastases, isolated tumor cells, and metastasis-negative. Meanwhile, the sensitivity for detecting micrometastases significantly improved with algorithm assistance, although the review time was significantly longer than that without assistance. Analysis of the algorithm's sensitivity in detecting metastasis in the reference standard indicated an area under the curve of 0.869, whereas that for the detection of micrometastases was 0.785. CONCLUSIONS: A wide variety of histological types in gastric adenocarcinoma could account for these relatively low performances; however, this level of algorithm performance could suffice to help pathologists improve diagnostic accuracy.

A case of metastatic renal cell carcinoma successfully treated with deferred cytoreductive nephrectomy following lenvatinib plus pembrolizumab combination therapy.

Introduction: Combination therapy using immuno-oncology drugs with tyrosine kinase inhibitors is increasingly important in the therapeutic strategy for metastatic renal cell carcinomas. Here, we report a case of metastatic renal cell carcinoma that was successfully treated with deferred cytoreductive nephrectomy following lenvatinib plus pembrolizumab combination therapy. Case presentation: A 49-year-old man was referred to our hospital with a diagnosis of advanced right kidney cancer with multiple lung metastases (cT3aN0M1). The size of the primary tumor was so huge that it exceeded 20 cm in diameter, pushing the liver and intestines to the left. After administration of lenvatinib and pembrolizumab combination as first-line treatment, all the metastatic lung lesions disappeared, and the primary lesion shrank significantly. Robot-assisted radical nephrectomy was successfully performed, resulting in complete surgical remission. Conclusion: Deferred cytoreductive nephrectomy following a lenvatinib plus pembrolizumab combination is a useful therapeutic strategy for achieving complete remission of metastatic renal cell carcinomas.

Complex glandular pattern is an aggressive morphology that predicts poor prognosis of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant neoplasm with various morphologies. Recognition of histological patterns that can predict prognosis is important in pathological examination. Recently, the complex glandular pattern was defined as a morphology associating the poor prognosis in lung adenocarcinoma. We investigated the significance of the complex glandular pattern in PDAC by performing a retrospective analysis. Among 240 consecutive cases of conventional PDACs, 21 cases in which complex glandular pattern constituted >50 % of the total tumor volume (CG-PDACs) were identified. The prevalence of CG-PDAC was 8.8 % among all preoperative therapy-naïve and surgically resected conventional PDACs. Compared to the control PDACs (n = 95), the CG-PDACs were characterized by significantly higher prevalence of small- to medium-sized artery invasion (71.4 % vs. 14.7 %, p < 0.0001), intratumoral necrosis (59.1 % vs. 16.8 %, p < 0.0001), tumor budding (mean: 15.5 vs. 12.5 per 0.785 mm2, p = 0.04), significantly higher Ki67 proliferative index (mean: 75.0 % vs. 54.7 %, p < 0.0001), and the HNF1α-/KRT81+ (quasi-mesenchymal) immunophenotype (42.9 % vs. 19.0 %, p = 0.004). In Kaplan-Meier analyses, the CG-PDAC patients achieved significantly worse disease-free survival (DFS) and overall survival (OS) compared to the control PDAC patients; the respective median DFS and OS were 6.3 and 17.7 months for CG-PDACs, and 22.6 and 52.8 months for control PDACs. A multivariate Cox regression analysis showed that predominance of complex glandular pattern was an independent prognostic factor (hazard ratio: 2.95; 95 % confidence interval: 1.46-5.98; p = 0.003). Our results provide new insights into the complex glandular pattern in conventional PDACs as a novel and potentially useful prognostic factor.